To identify alcoholism vulnerability and protective genes, we collected and tested for linkage and pattern of genetic transmission families from American Indian populations. Such populations are relatively homogeneous genetically and environmentally. This report addresses an American Indian tribe in which alcoholism is highly prevalent. A total of 582 subjects from a large family genealogy were psychiatrically interviewed (SADs-L), blind rated for diagnosis and genotyped. An analysis (J. Long) of the familiality of alcoholism revealed a significant increase in relative risk in first- degree relatives of alcoholics. In females, the risk was highest in first-degree relatives and still significant at the 3rd degree of genetic relationship. Binge drinking was evaluated with the result that this pattern of behavior was not, as has been alleged, benign or beneficial, but associated with dramatic increases in problems in multiple domains: social, violence/lawlessness, work and medical. Transmission analysis in the Southwestern Indian families showed, for the first time, that alcoholism in an American Indian tribe is familial, despite the high rate of alcoholism in this tribe (more than 50% of females and more than 85% of males). A whole autosome genetic linkage analysis on a subset of the sample utilized 517 short tandem repeat markers. By sib-pair analysis, strong evidence for linkage to alcohol dependence [DSM-III-R] was found near the chromosome 11p telomere [near the DRD4 dopamine receptor locus] and the centromeric region of chromosome 4p [near the GABA receptor cluster]. Simulation analyses confirmed that these linkage signals were statistically highly significant and they could, on a conservative basis, have been randomly expected in about one in six and one in three whole genome linkage analyses, respectively. A more modest linkage signal was also detected on chromosome 4q [at the location of the alcohol dehydrogenase gene cluster].